The present invention relates to chemical compounds that inhibit PTGES (also known as prostaglandin E synthase 1). Prostaglandin E synthase 1 is an enzyme that in humans is encoded by the PTGES gene (Polyak K, Xia Y, Zweier J L, Kinzler K W, Vogelstein B: Nature 389 (6648): 300-5; Jakobsson P J, Morgenstern R, Mancini J, Ford-Hutchinson A, Persson B: Protein Sci 8 (3): 689-92). PTGES is also known as mPGES-1 (microsomal prostaglandin E synthase 1) or PIG12, PP102, PP1294, MGST-IV, MGST1L1, TP53112, MGST1-L1.
PTGES is a member of the Membrane Associated Proteins in Eicosanoid and Glutathione metabolism (MAPEG) family of glutathione transferases, which also includes FLAP and LTC4 synthases (Murakami M, Nakatani Y, Tanioka T, Kudo I, Prostaglandins Other Lipid Mediat. 2002, 68-69: 383-99.; Park J Y, Pillinger M H, Abramson S B, Clin. Immunol. 2006, 119 (3): 229-40).
PTGES is an inducible enzyme that is strongly up-regulated in response to pro-inflammatory stimuli leading to strong and selective production of PGE2 in inflammatory conditions including arthritis, osteoarthritis and endometriosis (Sampey A V et al., Arthritis Res Ther. 2005; 7(3):114-7; Fahmi H., Curr Opin Rheumatol. 2004 16(5):623-7; Rakhila H. et al., Fertil Steril. 2013, 100(6):1650-9). PGE2 produced by PTGES is considered as a critically important and strong pro-inflammatory mediator of inflammation, pain, angiogenesis, fever, bone metabolism, cancer and atherosclerosis. PTGES is an inducible enzyme for the selective production of pro-inflammatory PGE2 from PGH2. PTGES represents, therefore, an attractive target to achieve more specific inhibition of PGE2 production while preserving production of other prostaglandins (Iyer J P et al., Expert Opin Ther Targets. 2009 July; 13(7):849-65).
LPS (lipopolysaccharide) induced peritoneal PGE production in murine macrophages is markedly reduced in murine knockouts of PTGES (Trebino et al., PNAS 2003, 100:9044-49). Genetic deletion or pharmacological inhibition of PTGES has been demonstrated to reduce inflammation and pain behavior in experimental animal models of pain (Trebino et al., PNAS 2003, 100:9044-49; Kamei et al., Journal of Biological Chemistry 2004, 279:33684-95; Kojima et al., Journal of Immunology 2008, 180:8361-6; Xu et al., Journal of Pharmacology and Experimental Therapeutics 2008, 326:754-63).
Non-steroidal anti-inflammatory drugs (NSAIDs) and Cyclooxgenase (COX2) inhibitors reduce pain and inflammation by inhibition of one or both isoforms of the COX enzymes leading to reduced formation of PGE2 and other prostaglandins. COX1 is a constitutively expressed enzyme in many cells whereas COX2 is induced by pro-inflammatory mediators e.g. cytokines in response to inflammation or tissue injury. COX enzymes metabolize arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2). PGH2 is further transformed to other physiological active prostaglandins including PGI2, PGD2, thromboxane A2, PGF2α and PGE2. In particular PGE2 has a role in pain, inflammation and fever responses (Samuelsson et al., Pharmacol Rev. 2007, 59(3):207-24; Iyer et al., Expert Opin Ther Targets 2009, 13(7):849-65).
Endometriosis is an inflammatory disease (Lousse J C, Van Langendonckt A, Defrere S, Ramos R G, Colette S, Donnez J. Front Biosci 2012, 4:23-40) and key PGE2 enzymes including COX2 and PTGES are up-regulated in human endometriotic lesions compared to the endometrium (Rakhila H. et al., Fertil Steril. 2013, 100(6):1650-9). Increased PGE2 levels are expected to contribute inflammatory pain symptoms in endometriosis patients.
Several lines of evidence also support a role of PTGES produced PGE2 in oncology and cancer diseases (Samuelsson et al., Pharmacological Reviews 2007, 59:207-224). High levels of PGE2 have been detected in various tumors, including colorectal cancer (Wang and DuBois, 2010 Oncogene 29: 781-788). PGE2 is involved in tumor progression by inducing proliferation, angiogenesis, invasion and metastasis in several solid tumors (Wang and DuBois, Nat Rev Cancer 2010, 10: 181-193). There are strong evidence provided in studies that PGE2 plays a key role in tumor promotion. Genetic deletion of PTGES in mice suppresses intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9) and suppresses tumor growth (Howe et al., Prostaglandins Other Lipid Mediators 2013, 106:99-105). PTGES is overexpressed in several cancer diseases in man such as in colorectal cancer (Yoshimatsu K et al., Clin Cancer Res. 2001, 7(12):3971-6; Yoshimatsu K et al., Clin Cancer Res. 2001, 7(9):2669-74), indicating a role in cancer diseases (Misra S, Sharma K, Curr Drug Targets. 2014, 15(3):347-59). Several lines of evidence also indicate that PGE2 is involved in cancer cachexia. It has been shown that IL-1beta induces anorexia by mechanism dependent on PTGES (Pecchi E et al., Physiol Genomics. 2006, 16; 25(3):485-92; Elander et al., American Journal of Physiology 2007, 292, 258-267). NSAIDs were partially effective in reversing chemotherapeutic induced anorexia in rats (Yamamoto et al., Br J Pharmacol. 2014, 171(11): 2888-2899) and a trend for a benefit of NSAID treatment in cancer cachexia patients has been shown (Solheim et al., Acta Oncol. 2013 52(1):6-17). PTGES knock-out mice exhibit resistance to tumor-induced anorexia and maintain their body mass (Pecchi E et al., J Neuroimmunol. 2008, 199, 104-114).
Hyperprostaglandin E syndrome or antenatal Bartter and classic Bartter syndrome belong to the heterogeneous group of hypokalemic salt-losing tubulopathies. PTGES expression is increased in patients with Bartter syndrome and Hyperprostaglandin E Syndrome with a selective increase of renal PGE2 level (Kömhoff et al., Pediatric Research 2004, 55, 261-266). Current therapeutic approach includes salt and water supplementation and Prostaglandin E2-synthase inhibition (Seyberth et al., Pediatr Nephrol. 2011, 26(10):1789-1802).
Reduction of PGE2 formation by inhibition of cycloxygenase-2 (COX2) has been shown to beneficial for non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus rats [Tian et al., PLoS One 2014, 3; 9(1)].
In order to avoid side effects associated with COX inhibition, a selective inhibition of the transformation of PGH2 to the pro-inflammatory PGE2 is expected to reduce pain and inflammatory responses while sparing the production of other physiological important arachidonic acid metabolites such as PGI2.
PGH2 is transformed to PGE2 by prostaglandin E synthases, including the two microsomal prostaglandin E synthases (PTGES and PTGES-2), and the cytosolic prostaglandin E synthase (PTGES-3).
Since PTGES functions as an inducible enzyme downstream of COX2, selective inhibition of PTGES is not expected to inhibit levels of e.g. PGI2 and thromboxane A2 and to maintain residual PGE2 levels produced by the two other prostaglandin E synthases PTGES-2 and PTGES-3. Accordingly, PTGES inhibition has the potential to relieve pain and inflammation while limiting any unwanted gastrointestinal or cardiovascular side effects.
Substituted Pyridyl-cycloalkyl-carboxylic acids have been disclosed in prior art for the treatment or prophylaxis of different diseases:
WO2005086661 discloses compounds, pharmaceutical compositions and methods useful for treating or preventing a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hyper-triglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema were described. WO2005086661 does not disclose cycloalkyl substituted linker L2.
WO2005049573 discloses compounds of Formula (I)
wherein one of R5, R6 and R7 is (Formula II)

The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are modulated by PPAR-delta and/or PPAR-alpha agonists. At least one or two of Y1-Y4 has/have to be nitrogen. A Phenyl ring has not been claimed as inner aromatic ring.
WO2002081428 describes benzene compounds represented by the following general formula (I),
which is useful as an insulin-resistant ameliorant. In the formula (I), X represents optionally substituted aryl or heteroaryl; Y represents a group represented by the general formula (II) (wherein RY1, RY2, and RY3 each represents hydrogen, etc.), etc.; Z represents a group represented by the general formula (III) (wherein m is 0 to 2 and RZ1, RZ2, RZ3, and RZ4 each represents hydrogen, etc.); and R1, R2, R3, and R4 each represents hydrogen, etc. Substituted pyridyl is not claimed for substituent X.
WO2011051165 discloses substituted 3-Phenylpropionic acids of formula (I)
and use thereof for the treatment and/or prophylaxis of cardiovascular diseases. In formula (I), R6 represents hydrogen, fluorine, chlorine, bromine, (C1-C4)-Alkyl, (C2-C4)-Alkenyl, cyclopropyl or cyclobutyl. Substituted pyridyl is not claimed for substituent R6.
WO2012076466 describes substituted 1-benzylcycloalkylcarboxylic acid derivatives of formula (I),
process for preparation thereof, the use thereof for treatment and/or prevention of disorders and the use thereof for production of medicaments for treatment and/or prevention of disorders, especially for treatment and/or prevention of cardiovascular disorders.
In the formula R8 represents fluorine, chlorine, bromine, nitro, cyano, trifluor-methoxy, acetyl, 2-cyanovinyl, (C1-C4)-alkyl, (C2-C4)-alkenyl, cyclopropyl or cyclobutyl, but not substituted pyridyl.
WO2012139888 discloses 3-phenylpropionic acid derivatives of the following formula,
carrying a branched or cyclic alkyl substituent at the 3-position, methods for the production thereof, the use thereof for treating and/or preventing illnesses, and the use thereof for producing pharmaceuticals for treating and/or preventing illnesses, in particular for treating and/or preventing cardiovascular diseases. R9 represents fluorine, chlorine, bromine, cyano, (C1-C4)-alkyl, (C2-C4)-alkenyl, cyclopropyl or cyclobutyl, but not substituted pyridyl.
WO2005086661 provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula Q-L1-P-L2-M-X-L3-A wherein the definitions of the variables Q, L1, P, L2, M, X, L3 and A are provided. The present invention also provides compositions and methods for use of the compounds, for instance, for treatment of type II diabetes. L2 does not represent cycloalkyl.Q-L1-P-L2-M-X-L3-A   I
WO2004099170 discloses compounds and pharmaceutically acceptable salts of formula (I):
which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-IB (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds have also been described.
L2 does not represent cycloalkyl.
U.S. Pat. No. 7,005,440 discloses the use of triaryl acid derivatives of formula (I)
and their pharmaceutical compositions as PPAR ligand receptor binders. These PPAR ligand receptor binders were described as useful agonists or antagonists of the PPAR receptor.
Pyridyl-cycloalkyl-carboxylic acids were generically covered by general formula (I). However, those compounds are neither specifically described nor exemplified. Additionally, U.S. Pat. No. 7,005,440 does not contain any statement about the usefulness of the said triaryl acid derivatives as PTGES inhibitors.
So, the state of the art described above does not describe the specific substituted Pyridyl-cycloalkyl-carboxylic acids of general formula (I) of the present invention as defined herein or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity.
It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.
In particular, said compounds of the present invention have surprisingly been found to effectively inhibit PTGES and may therefore be used for the treatment or prophylaxis of following diseases:                genitourinary, gastrointestinal, respiratory, proliferative and pain-related diseases, conditions and disorders;        gynecological diseases including primary and secondary dysmenorrhea, dyspareunia, endometriosis, and adenomyosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia; endometriosis-associated proliferation; pelvic hypersensitivity;        urinary tract disease states associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular Interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome;        cancer, cancer-related pain and cancer cachexia;        Epilepsy, partial and generalized seizures;        respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, bronchospasm;        gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like;        fatty liver disorders, in particular NASH (Non-Alcoholic Steato-Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders;        neurodegenerative disorders such as Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, Brain ischemia and traumatic brain injury;        pruritus;        Impaired wound healing and disease of the skeleton like degeneration of the joints, ankylosing spondylitis.        
Additionally, the compounds of the present invention are potent human PTGES inhibitors, interfering with inflammatory induced PGE2 levels.